Transdermal or topical plaster system with a polyacrylate matrix with improved physical properties

ABSTRACT

A transdermal or topical plaster system with a backing layer, with an active ingredient-containing and self-adhesive matrix based on crosslinkable polyacrylate as base polymer and with a removable protecting film is characterized by an at least two-layer matrix with a degree of crosslinking of the layer facing the skin which is appropriate for adequate adhesion to the skin thereof and is lower than the degree of crosslinking of the layer or layers on top thereof.

This application is a 371 of PCT/EP98/00685 Feb. 9, 1998.

The invention relates to a transdermal or topical plaster system with abacking layer, with an active ingredient-containing and self-adhesivematrix based on crosslinkable polyacrylate as base polymer and with aremovable protecting film.

Transdermal therapeutic systems (TTS) have now gained a firm place inthe therapy of some disorders because of the special advantages of thisadministration form for certain active ingredients. The plastersavailable on the market differ from one another in respect of theirtechnical construction and of the active ingredients, auxiliaries andpolymers employed.

In respect of technical construction, essentially two plaster systemsdominate the market at present. These are the so-called reservoirsystems and the so-called matrix systems. The reservoir systemstypically consist of a bag which is filled with a liquid preparation ofthe active ingredient. One side of the bag consists of a membrane whichis permeable at least for the active ingredient, and is normallyprovided with a suitable adhesive. In the matrix systems, the activeingredient is incorporated into a polymer formulation (matrix) which ispreferably also self-adhesive. Thus matrix systems consist in thesimplest case of a flexible sheet or textile fabric which form thebacking layer of the plaster, of one or more activeingredient-containing, preferably self-adhesive matrix layers and of aprotecting layer to be removed before use.

Matrix systems to a certain extent represent the second generation oftransdermal systems and are the preferred aim of new developments.Compared with reservoir systems, they have the advantage of greatercomfort of wearing and greater inherent safety because there is no needto worry about dose dumping due to leakage from the reservoir. Suchmatrix systems are also used as so-called topical systems, in which casethe active ingredient preferentially displays its effect at the site ofapplication, and systemic availability is not aimed at.

The preferred polymer class for formulating the matrix comprisespolyacrylate adhesives because they have a good adhesive power on theskin, are hypoallergenic and are available in a wide variety of typeswith different properties in respect of their physical and chemicalproperties.

The development of self-adhesive matrix systems is impeded by the factthat it is necessary to incorporate into the adhesive both the activeingredient and all the other auxiliaries such as, for example,permeation enhancers, and thus the properties of the adhesive arefrequently compromised. This affects in particular the cohesion of theadhesive, which is then manifested during storage thereof by so-calledcold flow and by adhesive residues remaining on the application sitewhen the plaster is removed from the skin.

Cold flow means in this connection that the adhesive matrix begins toflow like a very viscous liquid between the backing layer and protectinglayer during storage, and eventually the adhesive is no longercompletely covered by the backing layer. This may result, for example,in the plaster sticking to the primary packaging container, whichusually consists of a bag made from heat-sealed packaging materiallaminate, and thus becoming unusable.

These problems become particularly evident when the concentration ofplasticizing active ingredients and/or auxiliaries dissolved in theadhesive is more than 10 per cent by weight and the total weight of thematrix exceeds 50 g/m².

As means of suppressing this cold flow with polyacrylate adhesives, thepatent application WO 86/00814 provides for crosslinking of the polymerin such a way that the plasticizing action of the ingredients iscompensated by crosslinking. However, it must be remembered in thisconnection that the tack of the plaster decreases so greatly when thereis too much crosslinking that the adhesion to the skin becomesinadequate. Moreover the production of a plaster which adheres well andhas acceptable cold flow remains problematic.

The same applies to the solution proposed in the Patent DE 40 20 144, ofadding a film-forming nonadhesive polymer to the matrix.

The solution to the problem of improving the cohesion of the matrixwithout reducing the adhesive power on the skin has now surprisinglybeen found by constructing the matrix out of at least two layers whichhave, in particular, the same polymer composition and the sameconcentration of dissolved ingredients, where the layer(s) facing awayfrom the skin have a degree of crosslinking which is sufficient toprevent cold flow, and the layer facing the skin has a degree ofcrosslinking which guarantees sufficient adhesion to the skin.

Accordingly, the plaster system according to the invention of the typementioned at the outset is essentially characterized by an at leasttwo-layer matrix with a degree of crosslinking of the layer facing theskin which is appropriate for adequate adhesion to the skin thereof andis lower than the degree of crosslinking of the layer or layers on topthereof.

The coating weight of the skin contact layer is in this case preferably10-30 g/m². With such a thickness, the cold flow of the layer isnegligibly small, while the degree of crosslinking affords excellentadhesion to the skin.

Further particular features of the invention are evident from the claimsand the following description.

The crosslinking of the matrix layers to different extents can beeffected in a manner known per se, such as, for example, by

adding metal chelates such as, for example, aluminium

acetylacetonate or titanium acetylacetonate,

chemical crosslinking with reactive reagents such as, for

example, melamine,

crosslinking by electron irradiation,

irradiation with UV light in the case of adhesives with appropriatefunctional groups suitable for this purpose.

Particular benefits arise according to the invention from therecognition that two important parameters which are crucial for theperformance of the TTS are virtually unaffected by the degree ofcrosslinking. These are

a) the saturation solubility of all low molecular weight substances, andthus also of the active ingredient and

b) the diffusion coefficient of low molecular weight substances,

whereby the definitive elaboration of a specific plaster systemexperiences a considerable improvement.

The saturation solubility, and thus the thermodynamic activity, of theactive ingredient at a given concentration is unaffected because, ingeneral, only a very small portion of the functional groups on thepolymer which are necessary for the crosslinking participates in thecrosslinking reaction. Thus, the contribution of the functional groupsto the polarity of the polymer and thus also to its dissolving power isthus substantially retained. The diffusion coefficient of low molecularweight compounds remains substantially unaffected by the degree ofcrosslinking, because only the microviscosity of the polymer in theimmediate vicinity of the diffusing compound is of importance for thediffusion. However, this microviscosity is virtually unaffected, owingto the great length of the polymer molecules, at all degrees ofcrosslinking necessary in practice.

Thus, once the matrix formulation which is based on a self-adhesivepolyacrylate capable of crosslinking and which permits delivery of anamount, which is adequate for practical use, of active ingredientthrough the skin has been found, it is then possible directly to providea construction according to the invention of this matrix composed ofseveral layers with different degrees of crosslinking while optimizingthe thickness, cohesion and adhesive power, without thereby affectingthe permeation performance of the system.

This denotes a significant simplification for the development of matrixsystems. It is a simplification because problems with the adhesive powerand the cohesion frequently only become evident when the first clinicaltests and stability studies have already been carried out.Reformulation, necessary at this stage, of the matrix in respect of itscomposition has hitherto meant that the results of these clinical testsand the stability studies have been put in doubt. Optimization of thematrix in the sense of this invention means that the results of theclinical tests can be completely accepted and no additional stabilityrisks need be expected. This is made clear by means of the table shownbelow comparing permeation data for a plaster according to the inventionwith a two-layer matrix and a conventional plaster.

EXAMPLES FOLLOW TO ILLUSTRATE THE INVENTION. Example 1

Plastic with Scopolamine as Active Ingredient

12.5 g of oleyl alcohol and 12.5 g of scopolamine are added to 100 g ofa polyacrylate adhesive solution (Durotak 326-1753) with a solidscontent of 50%, and the solution is homogenized by stirring.

13.6 g of a 4 per cent solution of aluminium acetylacetonate in ethylacetate are added to 80 g of this solution, and the solution ishomogenized by stirring. The resulting solution is adhesive compositionA.

0.85 g of the 4% solution of aluminium acetylacetonate in ethyl acetateis added to 20 g of the active ingredient-containing adhesive solution,and the solutions are also homogenized by stirring. The resultingsolution is adhesive composition B with a lower metal chelateconcentration.

Adhesive composition A is spread with a knife on a siliconized polyestersheet in a thickness such that a coating weight of 80 g/m² results afterremoval of the solvents. The dried composition is laminated with a 25 μmthick polyester sheet.

Adhesive composition B is spread with a knife on a siliconized polyestersheet in a thickness such that a coating weight of 20 g/m² results afterremoval of the solvents.

The dried composition is laminated with the dried film described aboveafter removal of the siliconized sheet. It is now possible to cutfinished plasters out of the four-layer laminate produced in this wayand consisting of the 25 μm-thick polyester sheet, two differentlycrosslinked matrix layers and a siliconized polyester sheet.

The plaster produced in this way was subjected to a permeation studyusing a 0.127 mm-thick silicone membrane as model membrane for humanskin in order to show that a two-layer matrix system with differingdegrees of crosslinking in the sense of this invention shows virtuallyno difference from a conventional one-layer matrix system (made only ofadhesive composition A in a thickness of 100 g/m²) in respect of thepermeation rate for the incorporated active ingredient. The artificialmembrane was chosen in place of skin because the variability of naturalskin specimens makes it difficult to show small differences betweendifferent plaster formulations. Otherwise, the test was carried out withthe Franz diffusion cells described in the literature and known to theskilled person. The results of this test are shown in the table below.The amount of active ingredient incorporated and the active ingredientconcentration were the same in the two systems. However, the adhesivepower, and thus also the adhesive power on the skin, is significantlyimproved for the two-layer system according to the invention.

Permeated amount of scopolamine base [μg/cm²] after 0 h 2 h 4 h 6 h 8 h24 h 30 h 48 h 72 h One-layer 0 14.1 30.4 44.8 59.3 152.9 185.4 263.2355.8 plaster Two-layer 0 17.5 33.8 46.0 61.0 150.0 181.7 258.7 356.8plaster

Example 2

Plastic with Tiaprofenic Acid as Active Ingredient

6 g of oleic acid and 15 g of tiaprofenic acid are added to 100 g of apolyacrylate adhesive solution (Durotak 326-1051) with a solids contentof 50%, and the solution is mechanically stirred until all thetiaprofenic acid has dissolved.

15 g of a 4 per cent solution of aluminium acetylacetonate in ethylacetate are added to 80 g of this solution, and the solution ishomogenized by stirring. The resulting solution is adhesive compositionA.

2 g of the 4 per cent solution of aluminium acetylacetonate in ethylacetate are added to 20 g of the active ingredient-containing adhesivesolution, and the solution is also homogenized by stirring. Theresulting solution is adhesive composition B.

Adhesive composition A is spread with a knife on a siliconized polyestersheet in a thickness such that a coating weight of 100 g/m² resultsafter removal of the solvents. The dried composition is laminated with atransversely elastic viscose fabric. Adhesive composition B is spreadwith a knife on a siliconized polyester sheet in a thickness such that acoating weight of 25 g/m² results after removal of the solvents. Thedried composition is laminated with the dried film described above afterremoval of the siliconized sheet. The finished plasters can now be cutout of the four-layer laminate produced in this way and consisting ofthe viscose fabric, two differently crosslinked matrix layers and asiliconized polyester sheet.

What is claimed is:
 1. Transdermal or topical plaster system consistingof a backing layer, an active ingredient-containing and self-adhesivematrix, and a removable protective layer, said matrix consisting of atleast two layers which each consist of the same polymer compositionhaving a crosslinkable polyacrylate as base polymer, and the sameconcentration of dissolved ingredients, but no tackifying agent, whereinthe skin facing layer of the matrix has a coating weight of 10-30 g/m²,the crosslinking of which does not reduce the adhesion power to the skinthereof and is lower than the cold flow preventing degree ofcrosslinking of the layer or layers on top thereof.
 2. The plastersystem of claim 1 wherein the matrix has a total coating weight of atleast 50 g/m².